Current available retroviral vectors for gene therapy are based on murine and avian retroviruses. The efficiency gene transfers in primate primary cells by these vectors is very low and functional vectors are eventually lost. Therefore, novel gene therapy approaches to combat HIV infection will be limited as a result of inefficient delivery system. Since primate retroviruses replicate efficiently in primate cells a primate based retroviral vector will be a better system for antiviral therapy against HIV infection. Primate foamy viruses have several inherent features that make them ideal for gene transfer in primates. The foamy viruses are members of the spumaviriniae sub-family of retroviruses. Foamy viruses are found in many mammalian species including primates. These viruses appear to be non-pathogenic in their natural host even though virus is widely distributed in an animal and has been recovered from several organs and tissues including brain and peripheral blood leukocytes. Also, foamy viruses have a broad host range in cell culture with respect to cell type and species and can be propagated in cells such as epithelial and fibroblast cells as well as lymphoid cells and neural cells. A foamy virus isolate from one species can also infect other mammalian species. Thus, foamy viruses offer unique opportunities for developing viral vector systems to deliver genes into several cell types of many species. Recently, the genome of simian foamy virus type l (SFV-l) from rhesus macaque has been molecularly characterized by the Principal Investigator. The goal of this proposal is to develop a retroviral vector based on SFV- l for antiviral therapy against simian immunodeficiency virus (SIV) infection. SPECIFIC AIM 1: Packaging cell lines will be established, and SFV-l vectors with a selectable marker (neomycin) will be constructed. SPECIFIC AIM 2: The efficacy of SFV-l vectors will be tested in primate tissue culture cell lines and primary cells with emphasis on bone marrow cells. SPECIFIC AIM 3: SFV-l vector containing multiple ribozymes for SIV will be constructed and the antiviral activity of the multiple ribozymes will be tested. Ribozymes with multiple targets in the viral genome are expected to be effective inhibitors of SIV replication. Experimental outcomes from these studies will help device ribozyme based therapy with efficient vector system that prevent HIV infection.